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The Regulatory Roles of Phosphatases in Cancer

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The Regulatory Roles of Phosphatases in Cancer Oncogene (2014) 33, 939–953 & 2014 Macmillan Publishers Limited All rights reserved 0950-9232/14 www.nature.com/onc REVIEW The regulatory roles of phosphatases in cancer J Stebbing1, LC Lit1, H Zhang, RS Darrington, O Melaiu, B Rudraraju and G Giamas The relevance of potentially reversible post-translational modifications required for controlling cellular processes in cancer is one of the most thriving arenas of cellular and molecular biology. Any alteration in the balanced equilibrium between kinases and phosphatases may result in development and progression of various diseases, including different types of cancer, though phosphatases are relatively under-studied. Loss of phosphatases such as PTEN (phosphatase and tensin homologue deleted on chromosome 10), a known tumour suppressor, across tumour types lends credence to the development of phosphatidylinositol 3--kinase inhibitors alongside the use of phosphatase expression as a biomarker, though phase 3 trial data are lacking. In this review, we give an updated report on phosphatase dysregulation linked to organ-specific malignancies. Oncogene (2014) 33, 939–953; doi:10.1038/onc.2013.80; published online 18 March 2013 Keywords: cancer; phosphatases; solid tumours GASTROINTESTINAL MALIGNANCIES abs in sera were significantly associated with poor survival in Oesophageal cancer advanced ESCC, suggesting that they may have a clinical utility in Loss of PTEN (phosphatase and tensin homologue deleted on ESCC screening and diagnosis.5 chromosome 10) expression in oesophageal cancer is frequent, Cao et al.6 investigated the role of protein tyrosine phosphatase, among other gene alterations characterizing this disease. Zhou non-receptor type 12 (PTPN12) in ESCC and showed that PTPN12 et al.1 found that overexpression of PTEN suppresses growth and protein expression is higher in normal para-cancerous tissues than induces apoptosis in oesophageal cancer cell lines, through in 20 ESCC tissues. By performing IHC, high and low expression of downregulation of BCL2 resulting in changes in cell-cycle PTPN12 was found in 62.1% and 37.9% of ESCCs, respectively. progression. Moreover, they have shown that PTEN gene therapy Moreover, they demonstrated that patients with completely reduces tumour size in vivo, suggesting PTEN as an important resected ESCC and tumours with high PTPN12 expression biological marker. In addition, Hou et al.2 investigated the tumour had favourable survival compared with that of patients relationship of PTEN status and cell sensitivity to chemo- with low PTPN12, therefore proposing that PTPN12 can be used as therapeutic drugs in vivo. Esophageal squamous cell carcinoma an independent predictor of patient survival.6 (ESCC) cells transfected with or without the wild-type PTEN were You et al.7 evaluated the methylation levels of protein tyrosine inoculated subcutaneously into nude mice. Both wild-type PTEN phosphatase receptor type O (PTPRO) promoter as a potential and cisplatin could inhibit tumour growth and induce cell biomarker in ESCC. Their analysis revealed hypermethylated apoptosis. Cisplatin had the strongest inhibitory effects on PTPRO promoter status in 27 (75%) out of 36 primary tumours. tumours produced by cells transfected with wild-type PTEN, No methylated PTPRO was observed in normal peripheral blood indicating that PTEN can increase the in vivo sensitivity of ESCC samples from 10 healthy individuals. In addition, in PTPRO- cells to cisplatin. As further evidence of the importance of PTEN in silenced cell lines, expression was dramatically restored by oesophageal carcinogenesis, Ma et al.3 have recently found a treatment with the demethylating agent 5-azadC, confirming strong association of genetic polymorphisms in PTEN with high that DNA methylation is a mechanism regulating PTPRO risk of ESCC. expression and that aberrant methylation of the PTPRO In another study, immunohistochemistry (IHC) of 100 patients’ promoter is directly responsible for transcriptional inactivation of tumours with ESCC revealed that cell division cycle 25 homologue its expression in ESCC cell lines. These findings suggest that PTPRO A (CDC25A) and CDC25B phosphatases are strongly expressed in is a common target for epigenetic silencing via methylation in the cytoplasm of cancer cells.4 Furthermore, due to the role of ESCC and that its methylation may be involved in oesophageal CDC25B in cell growth, Dong et al.5 examined the levels of cancer tumourigenesis.7 Moreover, Motiwala et al.8 examined the CDC25B antibodies (abs) in sera from 134 oesophageal squamous levels of PTPRO methylation in blood cells, as the presence of cell carcinoma patients and determined that they are higher detectable methylated promoter DNA in blood cells has been compared with healthy subjects. Detection of CDC25B abs in reported to indicate the presence of circulating cancer cells during combination with traditional tumour markers (that is, the process of distant metastasis. Interestingly, PTPRO methylation carcinoembryonic antigen, squamous cell carcinoma antigen, occurred only in B-cell population of a subset of patients with cytokeratin fragment 21-1 (CYFRA21-1)) resulted in an increased chronic lymphocytic leukaemia, but not in normal B or sensitivity of detection, with 64.2% of patients testing positive for T lymphocytes, indicating that methylated PTPRO in blood cells at least one of these markers. Moreover, high levels of CDC25B is cancer-specific.8 Finally, a high frequency of PTPRO Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, UK. Correspondence: Dr G Giamas, Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK. E-mail: [email protected] 1These authors contributed equally to this work. Received 21 January 2013; accepted 1 February 2013; published online 18 March 2013 Phosphatases and cancer J Stebbing et al 940 hypermethylation in primary tumours significantly correlated with PTPN13 was shown to interact with the cytosolic domain of tumour stage, indicating that PTPRO methylation may also be Fas,39 while Miyazaki et al.40 reported that overexpression of involved in invasion of ESCC.7 PTPN13 enhances sensitivity to Fas-mediated apoptosis. However, Yao et al.41 demonstrated that expression of PTPN13 in 470% of Gastric cancer colon cancers was related to resistance against Fas-mediated apoptosis in vivo and in vitro. These contradictory reports reveal Insertion of cagA-protein from Helicobacter pylori into the gastric that PTPN13 may possess dual role in colon carcinoma, either as epithelial cells specifically binds and activates PTPN11 oncopro- an oncogene or as a tumour suppressor depending on the cellular tein.9,10 Activated PTPN11 induces cell growth and motility,11 context in which it is studied. while deregulation of PTPN11 by cagA induces abnormal Lassmann et al.42 evaluated distinct genomic DNA alterations proliferation and migration of gastric epithelial cells that leads using array comparative genomic hybridization and identified to gastric carcinogenesis.12 Several studies detected aberrant DNA DNA amplification of PTPN1 in 22% of the CRC cases, with the methylation of PTPN6 gene in gastric carcinomas. H. pylori highest percentage of changes in chromosomal-positive infection led to a decrease in the methylation levels in PTPN6,13 tumours. PTPN1 has been responsible for the activation and inconsistent with a previous report.14 Yang et al.15 reported that elevation of Src kinase activity in six human epithelial colon PTPN1 gene was amplified in gastric cancer tissues. With regards cancer cell lines.43 to the clinicopathological characteristics, PTPN1 was associated Enhanced Src activity mediates signals and directs downstream with tumour metastasis and tumour-node-metastasis stage, activation of the Janus kinase–signal transducer and activator of implicating its involvement in the development of gastric transcription (JAK-STAT) pathway. Signal transducer and activator cancer.16 As suggested, PTPN1 inhibitors may also be useful in of transcription 3 (STAT3) has been shown to be activated in colon the treatment of gastric cancer.17 tumours and cell lines.44,45 Protein tyrosine phosphatase receptor- PTPN3 and PTPN4 are two closely related non-receptor tyrosine type T (PTPRT) and protein tyrosine phosphatase receptor-type D phosphatases that are expressed in human gastric cancer cells and (PTPRD) were shown to be able to regulate STAT3.46,47 tissue specimens.18 PTPN3 dephosphorylates and cooperates with As aforementioned, the mutation screen established that PTPRT p38g, to form a complex that may increase Ras oncogenesis was the most frequently mutated PTP in colorectal carcinomas. through post synaptic density protein (PDZ)-mediated direct Zhang et al.46 demonstrated that PTPRT specifically regulates binding.19 The phosphatase activity of PTPN4 has been implicated phosphorylation of STAT3-Tyr 705 in CRC. Overexpression of PTPRT in the regulation of cytoskeletal events.20 Overexpression of activity inhibited cell growth, suggesting a tumour-suppressor PTPN4 in COS-7 (cells being CV-1 (simian) in Origin) cells role.27 In addition, paxillin, a direct substrate of PTPRT, can be decreased colony formation, inhibited cell growth and dephosphorylated at Tyr88, which is involved in cell–cell adhesion. decreased saturation density of these cells.21 Mutated PTPRT could promote CRC tumourigenesis and cell Wu et al.22 applied a reverse transcriptase–PCR-based protein migration,
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